The proposed research involves studying the effects of ethanol and its major metabolites, acetaldehyde and acetic acid, on the regulation of thyroid hormone economy at the level of the pituitary gland. These studies will be performed in two complementary model systems: (1) a cell culture system composed of a homogeneous population of thyrotropes and (2) the intact rat. The in vitro system will permit definition of the subcellular of molecular mechanisms involved in the action of ethanol and/or its metabolites, while the in vivo system will allow for correlative studies in the intact animal. Since there have been a number of observations in humans and in rats which suggest that ethanol and thyroid hormone affect cellular metabolism in similar fashions, this interacton will be investiated most completely. We will study the effects of ethanol and its metabolites on the intracellular metabolism of thyroid hormones by thyrotropes especially as it relates to increasing the conversion of thyroxine (T4) to triiodothyronine (T3) and to increasing the proportion of thyroid hormone on its nuclear receptor. We will also study the direct effects of ethanol on general metabolism of the thyrotrope and specifically TSH production in a thyroid hormone-free environment and compare them to the effects induced by thyroid hormones. Lastly, in experiments designed to correlate the changes observed in vitro with those found in the intact animal, we will study the effects of ethanol, administered acutely and chronically, on the production of TSH and its alpha and beta subunits in the rat. We will measure the levels of TSH and its subunits in the circulation, correlate them with changes in thyroid hormone levels and probe the status of thyrotrope function using stimulatory testing with thyrotropin releasing hormone (TRH). It is hoped that these studies will define the changes in thyroid hormone economy induced by ethanol at the pituitary thyrotrope and the intracellular or molecular mechanisms involved in these effects.